To Be or Not IIb: A Multi-Step Process for Epstein-Barr Virus Latency Establishment and Consequences for B Cell Tumorigenesis

Epstein-Barr virus (EBV), a gamma-herpesvirus, was the first human tumor virus discovered fifty years ago in endemic Burkitt lymphoma [1]. Surprisingly, EBV was subsequently recognized to be a ubiquitous virus infecting greater than 90% of adults worldwide. In healthy children, primary EBV infection is typically asymptomatic because of a robust T cell immune response. However, infection during adolescence or later can result in infectious mononucleosis. Regardless of the severity of primary infection, EBV establishes a lifelong latent infection in the peripheral blood memory B cell compartment [2]. Immune suppression, genetic predisposition, or environmental factors can all serve to promote EBV-driven tumors, which are primarily of B cell, but also of epithelial and NK or T cell origin. Early studies demonstrated that EBV infection in vitro transformed resting B cells into immortalized lymphoblastoid cell lines (LCL), providing a strong link to EBV-associated B cell cancers [3,4]. These pioneering studies stimulated intense investigation over the ensuing decades into the viral requirements and temporal cascade of gene expression triggering physiological cell changes associated with B cell proliferation and survival. The model that emerged indicates that B cell transformation in vitro is a latent infection including expression of a discrete set of nine proteins and many noncoding RNAs collectively called Latency III [2]. In this model, all of the Latency III gene products are expressed prior to the first cell division in the absence of lytic virus replication. However, this in vitro model does not account for the viral gene expression programs found in most EBV-positive B cell tumors or in the B cell compartment in vivo following natural infection. Moreover, a recent resurgence in studies of the earliest events following B cell infection combined with an appreciation of the heterogeneity of EBV latent gene expression during natural infection and in tumors provides the rationale for revisiting how this ubiquitous virus establishes latency and causes B cell malignancies.